Project Summary/Abstract Alzheimer's disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field is in dire need of novel drug targets which could lead to disease-modifying therapies. The most common genetic risk factor for AD is the ?4 variant of the apolipoprotein E gene (APOE4). The current study will take advantage of the strong effect of APOE4 to discover new genetic variants that either increase risk for AD or reduce risk for AD. The research team?based at Stanford University but including collaborators at 13 other research centers?will recruit and study participants that fall into one two rare categories: cognitively normal people carrying one or two copies of the high risk APOE4 gene (protected APOE4 carriers) and young patients who early-onset AD (EOAD) before age 65 despite not carrying APOE4 gene. These subjects, the Stanford Extreme Phenotypes in AD (StEP AD) cohort, will undergo whole-exome sequencing and their exomes will be combined with large, publicly available exomes from ~4500 healthy older controls and ~5000 AD patients. In Aim 1 the research team will look for rare genetic variants seen more often in protected APOE4 carriers than in AD patients. In Aim 2 the team will look for rare genetic variants seen in APOE4-negative EOAD patients but not in healthy older controls. Most of the StEP AD cohort will undergo ?deep phenotyping? to include structural and molecular brain imaging, spinal fluid analysis, immunophenotyping, and culturing of participant-specific neurons. In Aim 3, the deep phenotyping data will be used to begin to understand the molecular effects of the rare protective or causal genetic variants identified in Aims 1 and 2. Rare but powerful genetic variants identified and characterized in this study will provide novel drug targets for the design of potentially disease- modifying treatments.